Tianeptine

Tianeptine (INN) (Stablon, Coaxil, Tatinol) is a drug used for treating major depressive episodes (mild, moderate, or severe). It has structural similarities to the tricyclic antidepressants, but it has different pharmacological properties. Until recently, it has been assumed that tianeptine is a selective serotonin reuptake enhancer (SSRE), opposite to the action of SSRIs. However, newer studies question this hypothesis; one review suggests that long-term administration of tianeptine has no effect on serotonin pathways, while another still points to the cancellative effects of tianeptine and fluoxetine coadministration on serotonin reuptake. Tianeptine enhances the extracellular concentration of dopamine in the nucleus accumbens and modulates the D2 and D3 dopamine receptors, but this effect is modest and almost certainly indirect. There is also action on the NMDA and AMPA receptors. Recent reviews point to this pathway as a hypothesized mechanism of action, based on tianeptine's effect of promoting stress-associated impaired neuroplasticity.
Tianeptine reduces the effects of serotonin in the limbic system and the pre-frontal cortex, giving rise to a mood elevation, unlike the mood blunting associated with SSRIs.[citation needed] Like SSRIs, however, tianeptine's onset-of-action delay is approximately 2–6 weeks with improvements sometimes noticeable in as soon as one week. Its short-lived, but pleasant, stimulant effect experienced by some patients is shared with its predecessor, amineptine, whose side effects related to dopamine uptake inhibitor activity resulted in Servier's research into tianeptine.[citation needed] Suggested dosage is three times daily, due to its short duration of action.
Tianeptine has strong antidepressant and anxiolytic properties with a relative lack of sedative, anticholinergic and cardiovascular adverse effects, thus suggesting it is particularly suitable for use in elderly patients and in those following alcohol withdrawal; such patients can be more sensitive to the adverse effects of psychotropic drugs. Recent interesting results indicate anticonvulsant and analgesic activity of tianeptine and its possible interaction with adenosine A1 receptors.

Mechanism of action

Initial studies found that upon acute and sustained administration, tianeptine decreased the extracellular levels of serotonin. However tiapentine has low affinity for serotonin transporters, so this effect appears to be indirect. Further, the validity of the data from older studies has been contested on the basis of technical limitations; more recent studies found that long-term administration of tianeptine does not elicit any marked alterations (neither increases nor decreases) in extracellular levels of serotonin in rats, and tianeptine also had no effect on spontaneous firing rate of serotonergic neurons. However, coadministration of tianeptine and fluoxetine inhibited tianeptine's effect on long-term potentiation in hippocampal CA1 area. This is considered an argument for the opposite effects of tianeptine and fluoxetine on serotonin uptake.
In contrast to SSRIs and tricyclic antidepressants, tianeptine modestly enhances the mesolimbic release of dopamine, but it is also unclear how this occurs because tiapentine itself has no effect on dopamine transporters, nor does it affect D1, D2, D3, D4 and D5 receptors.
Perhaps the most studied hypothesis is that Tianeptine has a protective effect against stress induced neuronal remodeling. This is all based largely on preclinical studies.

Abuse and addiction potential

Abuse of tianeptine is rare and thus far has only been seen in patients with pre-existing multi-substance abuse disorders. 141 cases of abuse were identified between 1989 and 2004, correlating to an incidence of 1 to 3 cases per 1000 patients treated with tianeptine. The main reason for abuse is to achieve an anxiolytic effect. According to Servier, cessation of treatment with tianeptine is difficult, due to the possibility of withdrawal symptoms in a patient.
One patient reportedly consumed a total of 240 12.5 mg tablets (3000 mg) per day for several months and was later successfully detoxified in an inpatient setting. The report indicated that a tolerance was developed and there were physical withdrawal symptoms.
In 2007, according to French Health Products Safety Agency, tianeptine's manufacturer Servier agreed to modify the drug's label, following problems with dependency.
Singapore's Ministry of Health has restricted the use of tianeptine to psychiatrists due to its abuse potential, while Bahrain has classified it a controlled substance due to increasing reports of misuse and abuse by patients.
Tianeptine (under "Coaxil" brand name) has been intravenously injected by drug users in Armenia and Russia. This method of administration reportedly causes an opioid-like effect and is sometimes used in an attempt to lessen opioid withdrawal symptoms. As tianeptine tablets do not fully dissolve and often the solution is not filtered well, particles in the injected fluid can block small blood vessels, leading to thrombosis and then severe necrosis.

Approved

Tianeptine shows efficacy against serious depressive episodes (major depression), comparable to amitriptyline, imipramine and fluoxetine, but with far fewer side effects. It was shown to be more effective than maprotiline in a group of patients with co-existing depression and anxiety. Tianeptine also displays significant anxiolytic properties and is useful in treating a spectrum of anxiety disorders including panic disorder, as evidenced by a study in which those administered 35% CO2 gas (carbogen) on paroxetine (Paxil) or tianeptine (Stablon) therapy showed equivalent panic-blocking effects.

Investigational and ongoing research

Tianeptine has been reported to be very effective for asthma starting in August 1998, when Dr. Fuad Lechin and colleagues at the Central University of Venezuela Institute of Experimental Medicine in Caracas published the results of a 52-week randomized controlled trial of asthmatic children; the children in the groups that received tianeptine had a sharp decrease in clinical rating and increased lung function. Two years earlier, they had found a close, positive association between free serotonin in plasma and severity of asthma in symptomatic patients. As tianeptine was the only agent known to both reduce free serotonin in plasma and enhance uptake in platelets, they decided to use it to see if reducing free serotonin levels in plasma would help. By November 2004, there had been two double-blind placebo-controlled crossover trials, and a 25,000+ patient open-label study lasting over seven years, all showing effectiveness. A 2005 study in Egypt demonstrated tianeptine to be effective in men with depression and erectile dysfunction. Tianeptine also has anticonvulsant and analgesic effects, and a clinical trial in Spain that ended in January 2007 has shown that tianeptine is effective in treating pain due to fibromyalgia. Tianeptine is also being studied in the treatment of ADD/ADHD.
It is currently being researched for its effectiveness in irritable bowel syndrome.
Tinaneptine has been found to be effective in depression in Parkinson's disease and in post-traumatic stress disorder of which it was as safe and effective as fluoxetine (Prozac, an SSRI) and moclobemide (Aurorix, an MAO-A inhibitor).